-
Current Opinion in Structural Biology Dec 2016Autophagy is the process whereby cytosol, organelles, and inclusions are taken up in a double-membrane vesicle known as the autophagosome, and transported to the... (Review)
Review
Autophagy is the process whereby cytosol, organelles, and inclusions are taken up in a double-membrane vesicle known as the autophagosome, and transported to the lysosome for destruction and recycling. Electron microscopy (EM) led to the discovery of autophagy in the 1950s and has been a central part of its characterization ever since. New capabilities in single particle EM studies of the autophagy machinery are beginning to provide exciting insights into the mechanisms of autophagosome initiation, growth, and substrate targeting. These include EM structures at various resolutions of part of the Atg1 protein kinase complex and all of the class III phosphatidylinositol 3-phosphate complex I that initiate autophagy; the mTORC1 complex that regulates autophagy initiation; the Ape1 particle, a major substrate for selective autophagy in yeast; and p62, a mammalian selective autophagy adaptor. Equally exciting are the prospects for increased resolution and insight into autophagosome formation in cells from advances in cryo-EM tomography and focused ion beam-scanning electron microscopy (FIB-SEM). This review considers recent accomplishments, prospects for progress, and remaining obstacles that still need to be overcome.
Topics: Animals; Autophagosomes; Autophagy; Humans; Mechanistic Target of Rapamycin Complex 1; Microscopy, Electron
PubMed: 27614295
DOI: 10.1016/j.sbi.2016.08.006 -
Molecular Cell Oct 2019The clearance of surplus, broken, or dangerous components is key for maintaining cellular homeostasis. The failure to remove protein aggregates, damaged organelles, or... (Review)
Review
The clearance of surplus, broken, or dangerous components is key for maintaining cellular homeostasis. The failure to remove protein aggregates, damaged organelles, or intracellular pathogens leads to diseases, including neurodegeneration, cancer, and infectious diseases. Autophagy is the evolutionarily conserved pathway that sequesters cytoplasmic components in specialized vesicles, autophagosomes, which transport the cargo to the degradative compartments (vacuoles or lysosomes). Research during the past few decades has elucidated how autophagosomes engulf their substrates selectively. This type of autophagy involves a growing number of selective autophagy receptors (SARs) (e.g., Atg19 in yeasts, p62/SQSTM1 in mammals), which bind to the cargo and simultaneously engage components of the core autophagic machinery via direct interaction with the ubiquitin-like proteins (UBLs) of the Atg8/LC3/GABARAP family and adaptors, Atg11 (in yeasts) or FIP200 (in mammals). In this Review, we critically discuss the biology of the SARs with special emphasis on their interactions with UBLs.
Topics: Animals; Autophagosomes; Autophagy; Autophagy-Related Proteins; Binding Sites; Fungal Proteins; Humans; Ligands; Protein Binding; Protein Interaction Domains and Motifs; Signal Transduction; Ubiquitination; Ubiquitins; Yeasts
PubMed: 31585693
DOI: 10.1016/j.molcel.2019.09.005 -
International Journal of Molecular... Jun 2023Exosomes, which are extracellular vesicles (EVs) predominantly present in bodily fluids, participate in various physiological processes. Autophagy, an intracellular... (Review)
Review
Exosomes, which are extracellular vesicles (EVs) predominantly present in bodily fluids, participate in various physiological processes. Autophagy, an intracellular degradation mechanism, eliminates proteins and damaged organelles by forming double-membrane autophagosomes. These autophagosomes subsequently merge with lysosomes for target degradation. The interaction between autophagy and endosomal/exosomal pathways can occur at different stages, exerting significant influences on normal physiology and human diseases. The interplay between exosomes and the autophagy pathway is intricate. Exosomes exhibit a cytoprotective role by inducing intracellular autophagy, while autophagy modulates the biogenesis and degradation of exosomes. Research indicates that exosomes and autophagy contribute to the infection process of numerous enveloped viruses. Enveloped viruses, comprising viral nucleic acid, proteins, or virions, can be encapsulated within exosomes and transferred between cells via exosomal transport. Consequently, exosomes play a crucial role in the infection of certain viral diseases. This review presents recent findings on the interplay between exosomes and autophagy, as well as their implications in the infection of enveloped viruses, thereby offering valuable insights into the pathogenesis and vaccine research of enveloped virus infection.
Topics: Humans; Exosomes; Autophagy; Endosomes; Extracellular Vesicles; Autophagosomes
PubMed: 37445802
DOI: 10.3390/ijms241310618 -
Journal of Molecular and Cellular... Apr 2022Autophagy mediates cellular quality control mechanisms and energy homeostasis through lysosomal degradation. Autophagy is typically viewed as an adaptive process that... (Review)
Review
Autophagy mediates cellular quality control mechanisms and energy homeostasis through lysosomal degradation. Autophagy is typically viewed as an adaptive process that allows cells to survive against stress, such as nutrient deprivation and hypoxia. However, autophagy also mediates cell death during development and in response to stress. Cell death accompanied by autophagy activation and accumulation of autophagosomes has been classified as type II programmed cell death. Compared to the wealth of knowledge regarding the adaptive role of autophagy, however, the molecular mechanisms through which autophagy induces cell death and its functional significance are poorly understood. Autophagy is activated excessively under some conditions, causing uncontrolled degradation of cellular materials and cell death. An imbalance between autophagosome formation and lysosomal degradation causes a massive accumulation of autophagosomes, which subsequently causes cellular dysfunction and death. Dysregulation of autophagy induces a unique form of cell death, termed autosis, with defined morphological and biochemical features distinct from other forms of programmed cell death, such as apoptosis and necrosis. In the heart, dysregulated autophagy induces death of cardiomyocytes and actively mediates cardiac injury and dysfunction in some conditions, including reperfusion injury, doxorubicin cardiomyopathy, and lysosomal storage disorders. The goal in this review is to introduce the concept of autophagic cell death and discuss its functional significance in various cardiac conditions.
Topics: Apoptosis; Autophagosomes; Autophagy; Lysosomes; Myocytes, Cardiac
PubMed: 34919896
DOI: 10.1016/j.yjmcc.2021.12.006 -
Current Biology : CB Dec 2022Cellular homeostasis requires the swift and specific removal of damaged material. Selective autophagy represents a major pathway for the degradation of such cargo... (Review)
Review
Cellular homeostasis requires the swift and specific removal of damaged material. Selective autophagy represents a major pathway for the degradation of such cargo material. This is achieved by the sequestration of the cargo within double-membrane vesicles termed autophagosomes, which form de novo around the cargo and subsequently deliver their content to lysosomes for degradation. The importance of selective autophagy is exemplified by the various neurodegenerative diseases associated with defects in this pathway, including Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal dementia. It has become evident that cargo receptors are acting as Swiss army knives in selective autophagy by recognizing the cargo, orchestrating the recruitment of the machinery for autophagosome biogenesis, and closely aligning the membrane with the cargo. Furthermore, cargo receptors sequester ubiquitinated proteins into larger condensates upstream of autophagy induction. Here, we review recent insights into the mechanisms of action of cargo receptors in selective autophagy by focusing on the roles of sequestosome-like cargo receptors in the degradation of misfolded, ubiquitinated proteins and damaged mitochondria. We also highlight at which steps defects in their function result in the accumulation of harmful material and how this knowledge may guide the design of future therapies.
Topics: Ubiquitinated Proteins; Macroautophagy; Autophagy; Autophagosomes; Carrier Proteins
PubMed: 36538890
DOI: 10.1016/j.cub.2022.11.002 -
The Journal of Cell Biology Jun 2020Autophagosome biogenesis involves de novo formation of a membrane that elongates to sequester cytoplasmic cargo and closes to form a double-membrane vesicle (an... (Review)
Review
Autophagosome biogenesis involves de novo formation of a membrane that elongates to sequester cytoplasmic cargo and closes to form a double-membrane vesicle (an autophagosome). This process has remained enigmatic since its initial discovery >50 yr ago, but our understanding of the mechanisms involved in autophagosome biogenesis has increased substantially during the last 20 yr. Several key questions do remain open, however, including, What determines the site of autophagosome nucleation? What is the origin and lipid composition of the autophagosome membrane? How is cargo sequestration regulated under nonselective and selective types of autophagy? This review provides key insight into the core molecular mechanisms underlying autophagosome biogenesis, with a specific emphasis on membrane modeling events, and highlights recent conceptual advances in the field.
Topics: Autophagosomes; Autophagy; Autophagy-Related Proteins; Biological Transport, Active; Endoplasmic Reticulum; Humans; Lipid Metabolism; Lipids; Membranes; Signal Transduction
PubMed: 32357219
DOI: 10.1083/jcb.202002085 -
Autophagy Jul 2023Autophagosomes are crucial components of the cellular recycling machinery that form at endoplasmic reticulum (ER)-associated sites. As the autophagosome membrane is...
Autophagosomes are crucial components of the cellular recycling machinery that form at endoplasmic reticulum (ER)-associated sites. As the autophagosome membrane is largely devoid of transmembrane proteins, autophagosome biogenesis is thought to be largely regulated by lipid transfer and lipid modifications, as well as membrane-associated proteins. While the membrane origin of autophagosomes and their lipid composition are still incompletely understood, previous studies have found the autophagosome membrane to be enriched in unsaturated fatty acids and have little cholesterol, suggesting that cholesterol removal is an integral step during autophagosome biogenesis. In our study, we demonstrate that short term cholesterol depletion leads to a rapid induction of autophagy and identify the ER-localized cholesterol transport protein GRAMD1C as a negative regulator of starvation-induced macroautophagy/autophagy. ATG: autophagy related; ccRCC: clear cell renal cell carcinoma; ER: endoplasmic reticulum; GRAM: glucosyltransferases, RAB-like GTPase activators and myotubularins; GRAMD: GRAM domain containing; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MCBD: methyl-cyclodextrin; MTOR: mechanistic target of rapamycin kinase; VASt: VAD1 analog of StAR-related lipid transfer.
Topics: Autophagosomes; Autophagy; Carrier Proteins; Macroautophagy; Membrane Proteins; Cholesterol; Lipids
PubMed: 36469687
DOI: 10.1080/15548627.2022.2155020 -
The EMBO Journal Jan 2023In their recent article, Polyansky et al identify phosphatidylcholine (PC) as the most abundant lipid in the autophagosome membrane and demonstrate that eliminating de...
In their recent article, Polyansky et al identify phosphatidylcholine (PC) as the most abundant lipid in the autophagosome membrane and demonstrate that eliminating de novo PC synthesis sharply impairs autophagic processing. In the absence of PC synthesis, open cup-like structures accumulate, implicating PC as a key component in the closure of autophagosomes.
Topics: Autophagosomes; Phosphatidylcholines; Autophagy
PubMed: 36478568
DOI: 10.15252/embj.2022113046 -
The Journal of Cell Biology Mar 2019Macroautophagy involves the sequestration of cytoplasmic contents in a double-membrane autophagosome and their delivery to lysosomes for degradation. In multicellular... (Review)
Review
Macroautophagy involves the sequestration of cytoplasmic contents in a double-membrane autophagosome and their delivery to lysosomes for degradation. In multicellular organisms, nascent autophagosomes fuse with vesicles originating from endolysosomal compartments before forming degradative autolysosomes, a process known as autophagosome maturation. ATG8 family members, tethering factors, Rab GTPases, and SNARE proteins act coordinately to mediate fusion of autophagosomes with endolysosomal vesicles. The machinery mediating autophagosome maturation is under spatiotemporal control and provides regulatory nodes to integrate nutrient availability with autophagy activity. Dysfunction of autophagosome maturation is associated with various human diseases, including neurodegenerative diseases, Vici syndrome, cancer, and lysosomal storage disorders. Understanding the molecular mechanisms underlying autophagosome maturation will provide new insights into the pathogenesis and treatment of these diseases.
Topics: Animals; Autophagic Cell Death; Autophagosomes; Biological Transport, Active; Endoplasmic Reticulum; Humans; Lysosomes; Neurodegenerative Diseases
PubMed: 30578282
DOI: 10.1083/jcb.201810099 -
Cells Jan 2020In eukaryotic cells, autophagosomes and multivesicular bodies (MVBs) are two closely related partners in the lysosomal/vacuolar protein degradation system.... (Review)
Review
In eukaryotic cells, autophagosomes and multivesicular bodies (MVBs) are two closely related partners in the lysosomal/vacuolar protein degradation system. Autophagosomes are double membrane-bound organelles that transport cytoplasmic components, including proteins and organelles for autophagic degradation in the lysosomes/vacuoles. MVBs are single-membrane organelles in the endocytic pathway that contain intraluminal vesicles whose content is either degraded in the lysosomes/vacuoles or recycled to the cell surface. In plants, both autophagosome and MVB pathways play important roles in plant responses to biotic and abiotic stresses. More recent studies have revealed that autophagosomes and MVBs also act together in plant stress responses in a variety of processes, including deployment of defense-related molecules, regulation of cell death, trafficking and degradation of membrane and soluble constituents, and modulation of plant hormone metabolism and signaling. In this review, we discuss these recent findings on the coordination and crosstalk between autophagosome and MVB pathways that contribute to the complex network of plant stress responses.
Topics: Autophagosomes; Humans; Multivesicular Bodies; Plant Growth Regulators; Plants; Signal Transduction; Stress, Physiological
PubMed: 31947769
DOI: 10.3390/cells9010119